TY - JOUR
T1 - Prognostic value of automated KI67 scoring in breast cancer
T2 - A centralised evaluation of 8088 patients from 10 study groups
AU - Abubakar, Mustapha
AU - Orr, Nick
AU - Daley, Frances
AU - Coulson, Penny
AU - Ali, H. Raza
AU - Blows, Fiona
AU - Benitez, Javier
AU - Milne, Roger
AU - Brenner, Herman
AU - Stegmaier, Christa
AU - Mannermaa, Arto
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Sinn, Peter
AU - Couch, Fergus J.
AU - Devilee, Peter
AU - Tollenaar, Rob A.E.M.
AU - Seynaeve, Caroline
AU - Figueroa, Jonine
AU - Sherman, Mark E.
AU - Lissowska, Jolanta
AU - Hewitt, Stephen
AU - Eccles, Diana
AU - Hooning, Maartje J.
AU - Hollestelle, Antoinette
AU - Martens, John W.M.
AU - Deurzen, Carolien H.M.
AU - kConFab Investigators
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Jones, Michael
AU - Schoemaker, Minouk
AU - Wesseling, Jelle
AU - van Leeuwen, Flora E.
AU - Van 't Veer, Laura
AU - Easton, Douglas
AU - Swerdlow, Anthony J.
AU - Dowsett, Mitch
AU - Pharoah, Paul D.
AU - Schmidt, Marjanka K.
AU - Garcia-Closas, Montserrat
N1 - Funding Information:
The authors acknowledge support from Will Howat and Leigh-Anne McDuf-fus of the Cancer Research UK Cambridge Institute, University of Cambridge and from Lila Zabaglo of the Academic Biochemistry Laboratory of the Institute of Cancer Research, London during development of the automated scoring protocol. The authors wish to thank Heather Thorne, Eveline Nieder-mayr, all of the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia.
Funding Information:
The SEARCH study is funded by a programme grant from Cancer Research UK (C490/A10124. C490/A16561) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. Part of this work was supported by the European Community’s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009223175) (COGS). The authors acknowledge funds from Breakthrough Breast Cancer, UK, in support of MG-C at the time this work was carried out and funds from the Cancer Research, UK, in support of MA at the Institute of Cancer Research, London.
Funding Information:
The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007–3839; 2009 4363); BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The KBCP study was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland. The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 108419), the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). The MCBCS was supported by an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation, the Mayo Clinic Breast Cancer Registry and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. The ORIGO authors thank E. Krol-Warmerdam, and J. Blom; the contributing studies were funded by grants from the Dutch Cancer Society (UL1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The RBCS study was funded by the Dutch Cancer Society (DDHK 2004–3124, DDHK 2009–4318).
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/10/18
Y1 - 2016/10/18
N2 - Background: The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists' visual scores available in a subset of patients. Methods: We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors. Results: Patients in the highest quartile of KI67 (>12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31-2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86-1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16-5.27)) and node-positive (1.74 (1.05-2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02-2.84)). Model fit parameters were similar for visual and automated measures of KI67 in a subset of 2440 patients with information from both sources. Conclusions: Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment.
AB - Background: The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists' visual scores available in a subset of patients. Methods: We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors. Results: Patients in the highest quartile of KI67 (>12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31-2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86-1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16-5.27)) and node-positive (1.74 (1.05-2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02-2.84)). Model fit parameters were similar for visual and automated measures of KI67 in a subset of 2440 patients with information from both sources. Conclusions: Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment.
KW - Automated KI67
KW - Breast cancer
KW - Prognostication
KW - Visual KI67
UR - http://www.scopus.com/inward/record.url?scp=84992454911&partnerID=8YFLogxK
U2 - 10.1186/s13058-016-0765-6
DO - 10.1186/s13058-016-0765-6
M3 - Article
C2 - 27756439
AN - SCOPUS:84992454911
SN - 1465-542X
VL - 18
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 104
ER -
